The ability to generate complete genomic sequences will provide unique opportunities to explore how variation impacts evolution and human health, to discover mechanisms regulating organism development, and to manage disease diagnosis and intervention. The effective utilization of this genomic information requires a detailed understanding of the function of encoded information. While tremendous progress has been made in defining individual components of genomic sequences, we still do not understand the function of most annotated genes, we have a limited understanding of the role of non-coding sequences in gene regulation, and we have just started to define the contribution of genomic alterations to human disease. Our section directly addresses these issues by using genomic tools and genetic manipulation of model organisms to unravel genome function and to dissect gene regulatory pathways in development and disease. We integrate data from basic science with clinical information to: 1) identify pathways that regulate mammalian development, 2) understand how alterations in these pathways lead to disease states, and 3) develop paradigms for therapeutic interventions. Our group has demonstrated that mice heterozygous for mutations in the transcription factor SOX10 exhibit multiple defects in neural crest development including reduced numbers of melanocytes in the skin and absence of myenteric ganglia in the colon. We have also shown that SOX10 homozygous mutants die in utero and also exhibit extensive defects in the entire peripheral nervous system. The human congenital disorder Hirschsprung disease can be caused by SOX10 mutations, and it also exhibits rectocolic aganglionosis and can be associated with hypopigmentation. Thus SOX10 mice serve as mouse models for human disease as well as broadly inform us about neural crest development and disease. Our goal is to understand the function of SOX10 in mammalian development and use this information to understand the pathology of and develop treatments for neural crest disorders. 1. SOX10 and adult stem cell genetics. Hair graying in mouse is attributed to the loss of melanocyte stem cell function and the progressive depletion of the follicular melanocyte population. Single-gene, hair graying mouse models have pointed to a number of critical pathways involved in melanocyte stem cell biology; however, the broad range of phenotypic variation observed in human hair graying suggests that additional genetic variants involved in this process may yet be discovered. Using a sensitized approach, we ask here whether natural genetic variation influences a predominant cellular mechanism of hair graying in mouse, melanocyte stem cell differentiation. We developed an innovative method to quantify melanocyte stem cell differentiation by measuring ectopically pigmented melanocyte stem cells in response to the melanocyte-specific transgene Tg(Dct-Sox10). We make the novel observation that the production of ectopically pigmented melanocyte stem cells varies considerably across strains. The success of sensitizing for melanocyte stem cell differentiation by Tg(Dct-Sox10) sets the stage for future investigations into the genetic basis of strain-specific contributions to melanocyte stem cell biology. 2. HSCR and the immune system. Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers. ILC3 development is thought to be programmed, but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glialILC3epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals.